A Cancer Research UK Phase I Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Aurora B Inhibitor GSK1070916A in Patients With Advanced Solid Tumors

RATIONALE: Aurora B/C kinase inhibitor GSK1070916A (GSK1070916A) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of GSK1070916A in treating patients with advanced solid tumors.

开始日期2010-03-01

申办/合作机构

Cancer Research UK

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100 项与 NMI-900 相关的专利（医药）

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项与 NMI-900 相关的文献（医药）

2025-01-01·Neoplasia

Aurora kinase B is required for growth and expansion of medulloblastoma cells in the tissue context

Article

作者: Allalou, Amin ; Zhang, Hanqing ; Neuhauss, Stephan C.F. ; Neuhauss, Stephan C F ; Özalp, Özgün ; Santhana Kumar, Karthiga ; Grotzer, Michael A. ; Baumgartner, Martin ; Gries, Alexandre ; Kuttler, Fabien ; Grotzer, Michael A ; Akle, Veronica

The impact of the tissue context on tumor growth and drug response in medulloblastoma (MB) is poorly understood. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed the assessment of tumor cell behavior in the tissue context. To identify druggable kinase pathways involved in invasion, we screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB. Importantly, AURKBi are tumor suppressive in the tissue context, also in MB tumor cells that are in vitro resistant to the same treatment. We confirmed the requirement of AURKB for tumor growth and expansion in the tissue context through genetic suppression of AURKB by siRNA. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells. We demonstrate that tumor growth in the tissue context is suppressed by pharmacological inhibition of AURKB, comparable to the growth reduction observed after X-ray irradiation, which was used as the positive control. Finally, we show that exposure to µM concentrations of Barasertib does not cause developmental toxicity in fish larvae. In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.

2022-11-01·Annals of Translational Medicine

Clinical significance and immune landscape of cuproptosis-related lncRNAs in kidney renal clear cell carcinoma: a bioinformatical analysis

Article

作者: Zhang, Wenzhou ; Hao, Lidan ; Wu, Xuan ; Song, Wenping ; Li, Ding ; Cheng, Cheng

BackgroundKidney renal clear cell carcinoma (KIRC) is considered an immunogenic tumor. Cuproptosis is a newly identified copper-induced regulated cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) have emerged as significant players in tumorigenesis and metastasis. However, there is a huge knowledge gap on the prognostic role of cuproptosis-related lncRNAs in KIRC. And, the clinical value of them is still unknown. Here, we aimed to develop a cuproptosis-related lncRNA prognostic signature in KIRC.MethodsThe messenger RNA (mRNA)/lncRNA expression profiles and the clinical information including age, gender, tumor stage, grade, and overall survival (OS) were acquired from The Cancer Genome Atlas (TCGA) database. The included KIRC samples were further randomly assigned into training (n=258) or testing (n=257) data sets. We performed Pearson correlation analysis to identify the cuproptosis-related lncRNAs and then constructed the prognostic signature using Cox regression analysis and LASSO algorithm. Subsequently, Kaplan-Meier survival analysis, a nomogram, and receiver operating characteristic (ROC) curve were performed to assess the predictive performance of the signature. Moreover, the immune characteristics and drug sensitivity related to the signature were also explored.ResultsThe signature comprised 7 cuproptosis-related lncRNAs. The patients with a low-risk score had superior OS compared with those with a high-risk score. The survival rates of the high- and low-risk groups were 44.96% and 83.72% (P<0.001). The area under the curve (AUC) value for 1-, 3-, 5-year survival rate reached 0.814, 0.762 and 0.825, respectively. In addition, a nomogram was also generated; the AUC was 0.785 for risk score, higher than that for age (0.593), gender (0.489), grade (0.679), and stage (0.721). The high-risk group had more enriched immune- and tumor-related genes. Patients with low-risk scores were more sensitive to immunotherapy and the small molecular drugs GSK1904529A, tipifarnib, BX-912, FR-180204, and GSK1070916. Meanwhile, the high-risk group tended to be more sensitive to pyrimethamine, MS-275, and CGP-60474.ConclusionsCollectively, we constructed a cuproptosis-related lncRNA prognostic signature with a higher predictive accuracy compared to multiple clinicopathological parameters, which may provide vital guidance for therapeutic strategies in KIRC. Combination of more prognostic biomarkers may further improve the accuracy.

2022-08-21·Disease Markers

KDELR3 Is a Prognostic Biomarker Related to the Immune Infiltration and Chemoresistance of Anticancer Drugs in Uveal Melanoma

Article

作者: Yan, Shilong ; Yu, Lisha ; Zhang, Jingnan ; Zhang, Juan ; Guan, Jing

Uveal melanoma (UM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic diseases and have a poor clinical outcome. Immunotherapies are quickly becoming a need, and recent research has produced some amazing achievements in this area. In the current investigation, an attempt was made to evaluate the prognostic usefulness of KDELR3 in UM, particularly its connection with tumor-infiltrating lymphocytes (TILs). The expression patterns of mRNAs and related clinical data of 80 UM patients were obtained from The Cancer Genome Atlas (TCGA). By using RT-PCR, we were able to investigate whether or not UM cells and D78 cells expressed KDELR3. The Kaplan-Meier approach, as well as univariate and multivariate tests, was utilized in order to investigate the potential predictive significance of KDELR3 expression. The associations between KDELR3 and TILs and immunological checkpoints were analyzed in order to evaluate the effect that KDELR3 may have on UM immunotherapy. On the basis of the differential expression of KDELR3, a distribution of the half-maximal inhibitory concentration (IC50) of various targeted medicines was observed. In this study, we found that the expression of KDELR3 was distinctly increased in most types of tumors. In addition, KDELR3 was highly expressed in UM cells. Moreover, patients with high KDELR3 expression exhibited a shorter overall survival and disease-free survival than those with low KDELR3 expression. Multivariate analyses confirmed that KDELR3 expression was an independent prognostic factor for overall survival and disease-free survival in patients with UM. Furthermore, KDELR3 expression was demonstrated to be positively correlated with macrophage M1, T cell CD8, T cell follicular helper, dendritic cell resting, and T cell CD4 memory activated. Meanwhile, the expression of KDELR3 was related to several immune checkpoints. The IC50 of AP-24534, BHG712, bleomycin, camptothecin, cisplatin, cytarabine, GSK1070916, and tipifarnib was higher in the KDELR3 high-expression group. In conclusion, KDELR3 may be applied as a potential diagnostic and prognostic biomarker for UM patients.

100 项与 NMI-900 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床2期	-	GSK Plc	-
卵巢癌	临床前	美国	-	-
非小细胞肺癌	药物发现	美国	Nemucore Medical Innovations, Inc.	2019-07-14
费城染色体阳性慢性粒细胞白血病	药物发现	美国	Nemucore Medical Innovations, Inc.	2019-06-17
急性髓性白血病	药物发现	美国	Nemucore Medical Innovations, Inc.	2019-06-03
乳腺癌	药物发现	美国	Nemucore Medical Innovations, Inc.	2019-05-31
实体瘤	药物发现	英国	Cancer Research UK	2015-11-27
晚期恶性实体瘤	药物发现	英国	Cancer Research UK	2010-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01118611 (ASCO2013)	临床1期	实体瘤 \| HR阳性/HER2低表达实体瘤	38	GSK1070916A	(夢窪齋製廠窪鹽獵築願) = 齋獵壓鑰壓鹽顧鑰蓋顧選鬱膚範憲鏇範願鬱鹹 (願觸醖艱淵願簾窪齋鑰 )	-	2013-05-20